Orally administerable drugs for the treatment of central dopamine deficiency conditions

ABSTRACT

A drug formulation administrable by mouth for the treatment of central dopamine deficiency condition, said formulation comprising 
     100 to 250 parts by weight of levodopa, 
     10 to 25 parts by weight of carbidopa, 
     a polymer mixture in an amount of 10 to 200% based on said drugs, said polymer mixture consisting of: 
     0 to 100 parts by weight of a completely saponified polyvinyl alcohol having 0 to 3% residual acetyl content, a mean molecular weight of 60,000 to 80,000 and a total surface area of 0.1 m 2  /g to 0.18 m 2  /g, and 
     0 to 100 parts weight of a partially saponified polyvinyl alcohol having 10 to 18% residual acetyl content, a mean molecular weight of 80,000, a total surface area of 0.5 m 2  /g to 0.69 m 2  /g, and a specific pore volume of 0.2 cm 3  /g to 0.36 cm 3  /g, 
     and an effective amount of customary galenic adjuvants.

This application is a 371 of PCT/DE92/00043, filed Jan. 23, 1992.

This invention relates to orally administrable drug formulations, whichcontain a combination of the drugs levodopa and carbidopa in definedproportions, as well as a process for their manufacture. The inventionis useful in the pharmaceutical industry and makes available apharmaceutical preparation which can be used for treatment ofParkinson's disease.

BACKGROUND OF THE INVENTION

Serious disorders of the movement automatism, e.g., Parkinson's disease,occur frequently with increasing age.

The cerebral deficiency of neurotransmitters dopamine in the basalganglions of the brain of the diseased person, in particular, in thecorpus striatum, as a consequence of a nigrostrialis degeneration ofunknown etiology necessary for the extra pyramidal motoricity, leads toan imbalance between the dopaminogenic and cholinogenic neurotransmittersystems transmitting dopamine which brings about the coordination ofmovement.

A substitution of the missing biogenous amine can be achieved bysupplying its precursor levodopa, which penetrates the blood-brainbarrier; said levodopa being absorbed into the dopaminogenic neurons anddecarboxylated into dopamine. (Birkmayer, Hornkiewics, Wien, Klin.Wochenschrift 73 (1961), 787.) It is known that the peripheraldopadecarboxylation of levodopa by the simultaneous oral administrationof a suitable decarboxylase inhibitor, e.g., carbidopa (DE-PS 30 12 602,U.S. Pat. No. 3,769,424), or benserazide (DE-PS 32 35 093) is largelysuppressed, resulting in a distinct increase of the levodopa-serumlevel, which renders possible a relevant reduction of thetherapeutically necessary dosage and a decrease of associatedgastrointestinal and cardiovascular side effects.

The manufacture of capsules and film tablets containing levodopa andcarbidopa, and tablets capable of floating in the gastric fluid (GB-PS 1243 474, U.S. Pat. No. 4,424,235, BE-PS 894 376), is known. Furthermore,international standards have required, up to the present, a very fast invitro liberation (USP XXI). In addition, methods for the manufacture ofpharmaceutical preparations, from which the medicinal substanceslevodopa and carbidopa are released slowly and simultaneously, areknown. These pharmaceutical preparations, for example, can be polymermatrices (EP-PS 0 253 490, EP-PS 0 320 051), pellets (DE-PS 38 41 955,EP-PS 0 260 236, EP-PS 0 324 947), or also multi-layered molded shapes(EP-PS 0 302 693, EP-PS 0 314 206).

It is also known that the transformation of a medicinal substance, or ofa medicinal substance mixture, into a medicinal formulation is essentialfor influencing the bioavailability. At the same time, it is known tomake manageable very low drug dosages by means of suitablepharmaceutical adjuvants, or, as the case may be, to counteract drugincompatibilities in drug mixtures, or to guarantee the chemicalstability of one or several drugs. Furthermore, for the manufacture oftablets, a multitude of procedures are known, the aim of which is totransfer pulverized drugs, or mixtures of pulverized drugs andpharmaceutical adjuvants, into tablets under technical conditions. It isknown that, by means of an addition of suitable pharmaceutical adjuvantsto the drugs or the drug-adjuvant mixtures, it is possible to influenceand change the characteristics of the compositions, e.g., stability,electrostatic charge, flow characteristics and tabletingcharacteristics, as well as their bioavailability.

Also, filling hard gelatin capsules with medicinal substances containingpowder mixtures, granules, pellets, and similar materials, has beendescribed.

It is also known that by the addition of polyvinyl-alcohols, asignificant delay of the drug liberation can be obtained (DD-WP A 61K/309 487.4; U. Meyer, Diss., Berlin 1977), and that, in general,quickly decomposing solid tablets can be manufactured with polyvinylalcohol (W. Rietschel, "die Tablette," 104, Aulendorf, 1966).

DESCRIPTION

The considerable variability, in part, of the clinical picture ofParkinson's disease requires a sensible, individually adjustablemedicinal therapy.

On the one hand, drugs must be available to the therapeutic specialist,which correct, by an immediate complete liberation of the drugs levodopaand carbidopa, the transmitter deficiencies which have occurred in thecourse of a day, and consequently, produce a fast improvement in thepatient's total condition.

On the other hand, in a certain number of patients, also as aconsequence of the consistent drug release in a long-term therapy withconsequent high levodopa plasma levels, undesirable and unpleasant sideeffects occur which strongly impair the condition.

This invention has the object of developing a medicinal formulationwhich is periodically administrable by mouth, as well a process for itsmanufacture, according to which tablets and capsules can be manufacturedfrom levodopa and carbidopa, from which the drugs, in a release periodof about 30 to 45 minutes, are controlled and, over a further desiredperiod, are released completely and evenly, but without significantdelay.

According to the invention, this object is achieved by mixing 100 to 250parts by weight of levodopa and 10 to 25 parts by weight of carbidopawith a polymer mixture comprising 0 to 100 parts by weight of acompletely saponified polyvinyl alcohol and 100 to 0 parts by weight ofa partially saponified polyvinyl alcohol, in proportions of 10 to 200%based on the levodopa and carbidopa. To this drug-polymer mixture,customary pharmaceutical adjuvants are added in an amount which rendersit possible to manufacture the respective medicinal formulation in aknown manner, e.g., by direct tableting, tableting after granulationwith a suitable binding agent, or by filling into hard gelatin capsules.

Preferably, as polyvinyl alcohols, commercial products are used, thek-values of which (Fikentscher, Cellulosechemi 13 (1932), 58), forcompletely saponified polyvinyl alcohols lie in a range of 40 to 59,and, for partially saponified polyvinyl alcohols, lie in a range of 50to 59. Particularly suited are completely saponified polyvinyl alcoholswith 0 to 3 percent of vinylacetate content, a mean molecular weight of60,000 to 80,000, a total surface area of 0.1 m² /g to 0.18 m² /g andpartially saponified polyvinyl alcohols with 10 to 18 percent ofvinylacetate content, a mean molecular weight of 80,000, a total surfacearea of 0.5 m² /g to 0.69 m² /g and a specific pore volume of 0.2 cm³ /gto 0.36 cm³ /g.

Surprisingly, it has been found that the mixture according to thisinvention of the adjuvants and medicinal substances and the simplepharmaceutical-technological processing, which is possible through this,leads to the solution of the problem. It has been found furthermore thatthe levodopa/carbidopa-medicinal formulations obtained according to thisinvention by the use of combinations of polyvinyl alcohols of variousresidual acetate release the drugs quickly and completely, but in avariable or controllable manner as required.

The process according to this invention produces a drug formulationwhich releases both medicinal substances quickly and over a certainperiod at defined ratios and thus guarantees an optimum bioavailabilityof the peripheral dopadecarboxylase inhibitor carbidopa and the dopamineprecursor levodopa.

Accordingly, it is possible, for certain types of patients to produce,with a minimum expense, medicinal formulations with the optimum releasecharacteristics.

Thus, with the described drug formulation, it is possible to producelevodopa/carbidopa medicinal formulations, having either a swift andcomplete liberation, or, with an initially delayed liberation, asrequired.

EXAMPLES

Examples 1-12

Levodopa is mixed with carbidopa, a completely saponified polyvinylalcohol PVA-1 having a vinylacetate content of 2.5%, a mean molecularweight of 70,000, a total surface area of 0.14 m² /g and a k-value of55, with a partially saponified polyvinyl alcohol With a vinylacetatecontent of 15%, with a mean molecular weight of 80,000, with a totalsurface area of 0.57 m² /g, with a specific pore volume of 0.3 cm³ /gand a mean k-value of 55, called PVA 2 in the following, as well as withmagnesium stearate, and is directly molded into tablets with acompressing power of 10 to 15 kN.

Tested table formulations: See Table 1

In vitro drug liberation: See Table 2

Example 13

250 g levodopa, 25 g carbidopa, 25 g of a completely saponifiedpolyvinyl alcohol with a vinylacetate content of 3%, a mean molecularweight of 60,000, a total surface area of 0.104 m² /g and a k-value of45, 100 g cellulose powder with a grain particle size range of <0.16mm≧65% and <0.05 mm=10 to 30% and 5 g magnesium stearate are mixed andgranulated with 100 ml of a 2% gelatin solution in a vortex granulatorat 60° C., and are dried to a residual water content of 3 to 4%. Thegranulate is subsequently brought to a grain size of 1.2 mm by puttingit through a sieve, and then molded, with a set mass of 407 mg at acompressing force of 10 to 50 kN.

In vitro drug liberation: See Table 2

Example 14

250 g levodopa, 25 g carbidopa, 94 g cellulose powder with a grainparticle size range of <0.26 mm≧65% and <0.05 mm=10 to 30%, 3 g silicondioxide and 51 g PVA 1 are mixed in a vortex granulator, sprayed with 10ml of a 20% aqueous citric acid solution, and granulated with 150 ml ofa 5% aqueous solution of PVA 1, and simultaneously dried at atemperature of 60° C. to a residual water content of 3 to 4%.

The granulate, by means of sieving, is brought to its maximum grain sizeof 1.2 mm, mixed with 30 g of tallow and 5 g of magnesium stearate for15 minutes, and compressed with a compressing force of 10 to 50 kN, intotablets with a set mass of 440 mg.

In vitro drug liberation: See Table 2

Example 15

100 g levodopa, 25 g carbidopa, 16 g PVA 1, 5 g PVA 2, and 3 g ofsilicon dioxide are mixed in a vortex granulator, sprayed with 10 ml ofa 20% citric acid solution, and granulated with 75 ml of 10% of anaqueous solution of PVA 1 and dried simultaneously at a temperature of60° C. to a residual water content of 3 to 4%.

The granulate, by means of sieving, is brought to its maximum grain sizeof 1.00 mm, mixed with 90 g of cellulose powder with a grain particlesize range of <0.26 mm≧65% and <0.05 mm=10 to 30%, 10 g of tallow and 2g of magnesium stearate for 15 minutes, and filled each with 260 mg intoa hard gelatin capsule.

In vitro drug liberation: See Table 2

                  TABLE 1                                                         ______________________________________                                                                               Mg-                                           Levodopa  Carbidopa PVA 1 PVA 2 Stearate                               Example                                                                              mg        mg        mg    mg    mg                                     ______________________________________                                        1      100       10        100   10    5                                      2      100       25        100   25    5                                      3      150       15        150   15    5                                      4      250       25        250   25    5                                      5      250       25        25    100   5                                      6      250       25        125   0     5                                      7      250       25        0     125   5                                      8      250       25        100   25    5                                      9      100       25        2.5   10    5                                      10     100       25        12.5  50    5                                      11     100       25        25    100   5                                      12     100       25        50    200   5                                      ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Levodopa             Carbidopa                                                Time min.                                                                             15     30     45   60    15   30   45   60                            Example Drug %                                                                ______________________________________                                        1       82.3   95.4   99.0 101.0 81.4 93.5 99.2 100.0                         2       85.2   93.1   100.3                                                                              --    83.2 91.5 98.7 --                            3       83.6   94.4   100.1                                                                              --    84.7 86.4 99.0 --                            4       89.6   97.7   100.5                                                                              --    85.3 97.6 100.4                                                                              --                            5       42.1   69.2   86.9 100.2 33.6 70.4 91.2 98.0                          6       87.3   98.1   100.0                                                                              --    86.7 87.2 103.0                                                                              --                            7       35.2   45.4   70.9 82.9  34.9 46.6 69.2 80.1                          8       74.7   86.3   95.1 103.0 74.2 83.3 98.4 --                            9       47.2   75.5   93.7 98.3  42.9 75.1 92.8 98.4                          10      43.6   73.5   100.0                                                                              --    40.2 73.0 92.9 98.7                          11      32.4   44.2   59.4 68.3  30.7 40.3 53.6 61.4                          12      27.7   38.6   53.1 64.8  28.6 37.4 51.1 65.8                          13      74.3   98.6   102.0                                                                              --    87.0 100.0                                                                              --   --                            14      89.2   92.1   93.0 94.2  85.2 90.4 92.6 95.4                          15      86.4   94.1   98.9 99.7  84.8 92.3 98.1 100.1                         ______________________________________                                    

For examples 7, 11, and 12, the extent of liberation of the drug wastested for periods beyond 60 minutes:

    ______________________________________                                                Levodopa          Carbidopa                                           Example   90 min. 120 min.    90 min.                                                                             120 min.                                  ______________________________________                                        7         103.0   --          100.0 --                                        11        85.6     99.1       86.3  102.2                                     12        86.4    100.0       84.5   98.6                                     ______________________________________                                    

What is claimed is:
 1. Drug formulation administrable by mouth for the treatment of central dopamine deficiency conditions, said formulation comprising100 to 250 parts by weight of levodopa, 10 to 25 parts by weight of carbidopa, a polymer mixture in an amount of 10 to 200% based on said drugs, said polymer mixture consisting of: 0 to 100 parts by weight of a completely saponified polyvinyl alcohol having 0 to 3% residual acetyl content, a mean molecular weight of 60,000 to 80,000, and a total surface area of 0.1 m² /g to 0.18 m² /g, and 100 to 0 parts per weight of a partially saponified polyvinyl alcohol having 10 to 18% residual acetyl content, a mean molecular weight of 80,000, a total surface area of 0.5 m² /g to 0.69 m² /g, and a specific pore volume of 0.2 cm³ /g to 0.36 cm³ /g, and an effective amount of customary galenic adjuvants.
 2. Drug formulation administrable by mouth for the treatment of central dopamine deficiency conditions, said formulation comprising100 to 250 parts by weight of levodopa, 10 to 25 parts by weight of carbidopa, and 10 to 200%, based on said drugs, of a completely saponified polyvinyl alcohol having a residual acetyl content of up to 3%, a mean molecular weight of 60,000 to 80,000, and a total surface area of 0.1 m² /g to 0.18 m² /g, or a partially saponified polyvinyl alcohol, or a mixture thereof.
 3. Drug formulation according to claim 2 comprising a mixture of the completely saponified polyvinyl alcohol and the partially saponified polyvinyl alcohol.
 4. Drug formulation administrable by mouth for the treatment of central dopamine deficiency conditions, said formulation comprising100 to 250 parts by weight of levodopa, 10 to 25 parts by weight of carbidopa, and 10 to 200%, based on said drugs, of a completely saponified polyvinyl alcohol having a residual acetyl content of up to 3%, or a partially saponified polyvinyl alcohol having a residual acetyl content of 10% to 18%, a mean molecular weight of 80,000, a total surface area of 0.5 m² /g to 0.69 m² /g, and a specific pore volume of 0.2 cm³ /g to 0.36 cm³ /g, or a mixture thereof.
 5. Drug formulation according to claim 4 comprising a mixture of the completely saponified polyvinyl alcohol and the partially saponified polyvinyl alcohol. 